The research proposed in this ADAMHA Research Science Development Award application tests the hypothesis that the ovarian hormones estradiol E2 and progesterone (P) regulate norepinephrine (NE) signal transduction in the neuronal populations which control reproduction. Preliminary work from this laboratory demonstrates that the functional activity of alpha 1 and beta-adrenergic receptors, as reflected by stimulation of brain slice cAMP accumulation and membrane adrenylyl cyclase (AC) activity, is modulated E2 and P female rat hypothalamus and preoptic (POA). E2 attenuates beta- receptor activation of AC and concomitantly increase alpha 1 receptor potentiation of cAMP accumulation in hypothalamic and POA slices. The changes are correlated with modest increases in alpha 1 receptor number but no alteration in beta receptor number or antagonist binding affinity. In slices from E2-primed females, P abolishes alpha 1 receptor augmentation of cAMP synthesis without measurably decreasing alpha 1 receptor binding. Therefore, studies described in this proposal are designed identity the mechanism underlying ovarian steroid regulation of alpha and beta adrenergic receptors in the hypothalamus and POA. Specific hypotheses to be addressed include: A. The alpha adrenergic receptor is a gene product whose expression is regulated by E2-receptor interactions and which is subject to homologous desensitization by P. The following studies will test this hypothesis: (1) Is E2 elevation of alpha 1 receptor number confined to regions of hypothalamus and POA that express E2 receptors and correlated with hormonal facilitation of estrous behavior? (2) Does E2 regulate the level of alp 1 receptor mRNA in regions of the hypothalamus and POA that express E2 receptors? (3) Does P abolish alpha 1 receptor augmentation of cAMP formation in slices from E2-primed rats by modifying alpha 1 receptor coupling to G proteins? (4) Are E2 and P regulation of alpha 1 receptor augmentation of cAMP formation correlated with alterations in alpha 1 receptor coupling to the phosphoinositol second messenger system? B. E2 promote homologous desensitization of beta-adrenergic receptor activation of AC via E2-receptor-mediated interactions. The following studies will test this hypothesis: (1) Does E2 have selective effects on beta 1 and or beta 2 receptor number in discrete hypothalamic regions? (2) Is E2 attenuation of B receptor stimulation of AC mediated by E2-receptor within brain cell nuclei? (3) Does E2 inhibit Beta- adrenergic activation of cyclase by modifying beta receptor coupling to G proteins? (4) Is E2 desensitization of beta-adrenergic coupling to AC correlated with increased expression of beta-arresting mRNA?